Effect of a vitamin D-3 analogue on keratinocyte growth factor-induced cell proliferation in benign prostate hyperplasia

Prostate enlargement and function is under the dual control of androgens an d intraprostatic growth factors. They regulate, in concert, prostate cell p roliferation and apoptosis. An increased signaling of both growth factors a nd androgens are supposed to underlie benign prostate hyperplasia (BPH), on e of the more common disorders of the aging male. Since, in clinical practi ce, androgen ablation resulted in a rather limited decrease in prostate vol ume, therapeutic strategies targeting intraprostatic growth factors are eme rging. The activated form of vitamin D, vitamin D-3, and some of its analog ues have been described as potent regulators of cell growth and differentia tion. In this study, we report the effects of one of these vitamin D, analo gues, 1,25-dihydroxy-16ene-23yne D-3, or analogue (V), on the fate of isola ted epithelial cells derived from patients with BPH. We essentially found t hat analogue (V), as well as vitamin D-3, inhibited BPH cell proliferation and counteracted the mitogenic activity of a potent growth factor for BPH c ells, such as keratinocyte growth factor (KGF). Moreover, analogue (V) indu ced bcl-2 protein expression, intracellular calcium mobilization, and apopt osis in both unstimulated and KGF-stimulated BPH cells. Since a short-term (5-min) incubation with analogue (V) reduced the KGF-induced tyrosine phosp horylation of a 120-kDA protein, corresponding to the KGF receptor, a rapid and direct cross-talk between these two molecules is suggested. Such a rap id effect of analogue (V), together with the transient induction of intrace llular calcium waves, seems to indicate the partial involvement of a membra ne, nongenomic receptor for vitamin D-3. In conclusion, we demonstrated the antiproliferative and proapoptotic effect of analogue (V) in BPH cells and speculated on its possible use in the therapy of BPH.